Methods for lowering blood cholesterol



United States Patent 3,245,878 METHODS FGR LOWERING BLOOD CHOLESTEROLFrank M. Berger, 227 Prospect Ave, Princeton, N.J., and

Bernard J. Ludwig, 1159 Stockton Place, North Brunswick, NJ.

No Drawing. Filed July 17, 1963, Ser. No. 295,807

19 Claims. (Cl. 167-65) This application is a continuation-in-partapplication of now abandoned application Serial Number 164,856, filedJanuary 9, 1962, which in turn is a continuation-inpart application ofapplication Serial Number 83,954, filed January 23, 1961, now abandoned.

This invention relates to novel compositions of matter and methods forlowering blood cholesterol.

Objects and advantages of the invention will be set forth in parthereinafter and in part will be obvious herefrom, or may be learned bypractice with the invention, the same being realized and attained bymeans of the steps, methods and compositions pointed out in the appendedclaims.

The invention consists in the novel steps, methods and compositionsherein shown and described.

It is an object of this invention to provide novel compositions ofmatter which have the effect of lowering blood cholesterol uponadministration of such compositions to warma'blooded animals. A furtherobject of this invention is to provide a novel method of lowering bloodcholesterol in warm-blooded animals. A further object of this inventionis to provide novel compounds which are useful as active ingredients incompositions useful in lowering blood cholesterol in warm-bloodedanimals.

It has been found that some of the objects of this invention may berealized by employing as the active ingredient for reducing bloodcholesterol a compound selected from the group consisting of (1)compounds having the formula:

wherein X is selected from the group consisting of hydrogen, lower alkyland halogen; Y is selected from the group consisting of hydrogen,

I i i i iR, -iJOR, CNH2 and CNHCR wherein R is selected from the groupconsisting of alkyl and aryl; and Z is selected from the groupconsisting of hydrogen and aralkyl; (2) compounds having the formula:

CH2ON X1 Zr wherein X is a lower alkoxy group; Y is selected from thegroup consisting of hydrogen,

i i C R1 and COR1 wherein R is selected from the group consisting ofalkyl and aryl; and Z is an aralkyl group; and (3) compounds having theformula:

CHzON wherein X is a trifiuoromethyl group; Y is selected from the groupconsisting of wherein X is selected from the group consisting ofhydrogen and lower alkyl; Y is selected from the group consisting ofhydrogen and 0 Jim wherein R is selected from the group consisting ofalkyl and aryl; and Z is an aralkyl group.

When the above compounds are amines, that is, when Y, Y or Y ishydrogen, they may also be employed in the form of their physiologicallyacceptable salts such as the hydrohalides (preferably thehydrochloride), salts with other readily tolerated inorganic acids suchas sulfuric or phosphoric acid, and salts with the commonly used organicacids such as acetic, citric, maleic, and tartaric acid.

For convenience sake, compounds having the aforedescribed chemicalstructures will be referred to hereinafter as aralkoxyamine compounds.

Examples of aralkoxyamine compouds which are the preferred activeingredients of the present invention are shown in Table A givenhereinafter. Examples of different types of aralkoxyamine compoundsuseful as the active ingredients of this invention, including thepreferred active ingredients of Table A, are given in Tables B to Hgiven hereinafter.

As indicated hereinbefore, it has been found that the aralkoxyam-inecompounds used in accordance with this invention when taken internallyhave the effect of lowering the :blood cholesterol content, e.g., theamount of cholesterol in the blood of the warm blooded animal taking theactive ingredients of the present invention. In forming the novelcompositions of this invention, the active ingredient is incorporated ina suitable carrier such .as, for example, a pharmaceutical carrier,beverage or food-stuff. Any suitable pharmaceutical carrier may be usedfor formulating the compositions of this invention, such as, forexample, starch, lactose, glucose, sucrose, gelatin, powdered licorice,powdered marshmallow, powdered tnagacanth, malt, rice flour, powderedalthaea, magnesium carbonate, chalk, and the like. Among the liquidpharmaceutical carriers which may be utilized are ethyl alcohol,propylene gylcol, polyethylene glycol, water, saline, glycerine andwater mixtures, glucose syrup, honey, mucilage of acacia, syrup ofacacia, mucilage of t-ragacanth, glyceride of starch, etc. Also, theactive ingredient may be incorporated in a foodstuff such, for example,as incorporating it in butter, margarine and the like. The preferredcarrier fora given active ingredient depends upon the desired use andnature of the active ingredient. For example, a liquid active ingredientis prefer-ably administered in the form of a soft gelatin capsulecontaining a therapeutic dose of [the active ingredient. A crystallinesolid active ingredient is prefer ably administered in the form of acapsule or tablet. When the composition of this invention is in the formof a solid, the active ingredient is generally in an amount from about25 to 95% by weight of the solid composition. When the composition ofthis invention is in the form of a solution, the active ingredient isgenerally in an amount of from about 0.1 gram to 90* grams per 100 gramsof solution.

An invivo technique which has been valuable in the determination ofcholesterol lowering action of drugs is the procedure of Outhbertson etal., 1959 (British J. Nutrition, volume 13, page 227). Using theformulation given by these investigators, a stock diet (A) which isessentially normal rodent diet comparable to that available fromcommercial feed dealers, and a special high fat diet (B) are prepared.The B diet features 2% cholesterol; 0.5% cholic acid; and speciallyprepared hydrogenated arachis oil, 22%; also corn starch, 45.5%; crudecasein, 25%; choline chloride, 1%; and salt and vitamin mixtures. Thehydrogenated arachis oil specifies a 92 F. melting point with limits of9093 F. Drugs to be evaluated are added to Diet B at fixed gradedconcentrations in the diet, ranging from 0.125 to 2%. Male Charles Riveralbino weanling rats weighing approximately 50 grams are placed inindividual cages equipped with specially designed self-feeder deviceswhich permit accurate determination of daily food intake. Groups of sixanimals, kept in individual cages, receive each of the concentrations ofdrugs. In addition, a group of six on the stock diet (A) serves as anegative control, and a high fat diet (B) group of six serves as apositive control. The rats are placed on (the special diets for fourteenconsecutive days, after which time one to three milliliter blood samplesare obtained. by intraoardiac puncture, and subjected to assay for theircholesterol content. The animals serving as the negative control group(Diet A) maintain a cholesterol level in the normal range which is lessthan 100 mg./100 ml. of serum, whereas the positive control group (DietB) show .a marked elevated level of the order of 800 mg./1-00 ml.

The active ingredients used in accordance with this invention, whenincorporated in Diet B following the above described Cu'thbertson et a1.method, exhibit a cholesterol lowering activity. In general, when suchactive ingredients arein concentrations of about 0.25 to about 0.5% inDiet B, the percent reduction in the blood cholestterol level is about25% or more as compared to the positive control ("Diet B) without theactive ingredient. Thus, if a positive control group given Diet B showsa blood cholesterol level of about 800 m-g./ 100 ml., the activeingredients of this invention, if incorporated in such Diet B, in aconcentration of about 0.25 to about 0.5 would generally reduce theblood cholesterol level of this positive group to about 600 mg./ 100 ml.or lower. Effective drugs usually show a direct relationship between theconcentration of drug in the diet, and the percent reduction in theblood cholesterol levels as compared to the positive control (Diet Bwithout drug).

While the laforede-scribed in vivo method of Cuth-bertson et al. is thepreferred procedure for determining the eifioacy of an agent regardingits cholesterol lowering activity, the in vitro method based on theprocedure described by N. L. R. Bucher in the Journal of the AmericanChemical Society, vol. 75, p. 498 (1953), has also been found useful forthis purpose. This in vitro procedure employs radioactive techniques andmeasures the ability of a compound to inhibit the conversion of acetateor other cholesterol precursors to cholesterol using liver homogenate asa source of the enzyme system. Compounds which -are effective inpreventing cholesterol formation under these conditions would presumablybe effective in bringing about a lowering of the serum cholesterolcontent of the animal.

2 g. of liver from freshly killed Sprague-Dawley rats is homogenized atC. in a medium containing 8.5 mgm. nicotinamide, 3.5 mgm. magnesiumchloride, 3.2 mgm. glutathione, and 3.0 mgm. ethylenediaminetetraaceticacid tetrasodium salt in 2.5 ml. of 0.1 M phosphate butter, pH 7.4. Thehomogenate is centrifuged at 0 and 2 ml. of the supernatant liquid, freefrom hepatic cells, is combined with 1 mgm. adenosine triphosphate, 1mgm. diphosphopyridine mucleotide, 0.5 mgm. of the compound under test,and 1 m1. of sodium acetate l-C solution containing 0.2 mgm. of acetatewith a count of about 2 microcuries of radioactivity. Controls areprepared in the same manner except that no compound is added. Allcompounds are run in triplicate.

The biosynthesis of cholesterol is effected by incubating the abovemixture in a metabolic shaker for three hours at 37 C. under anoxygen-carbon dioxide mixture (9525). After three hours the mixture istransferred to a glass ampoule where it is subjected to saponificationalong with 0.5 mg. of carrier cholesterol using 6 ml. of 15% alcoholicpotassium hydroxide at 80 C. for 17 hours. After removal of the alcoholthe cholesterol is isolated by extracting four times with petroleumether. The extracts are combined, dried, and evaporated to dryness. Theresidue is dissolved in 1 ml. of hot 80% ethanol and treated with anexcess of 1% digitonin, also in 80% ethanol, and heated for 5 minutes at100 C. After standing for 12 to 18 hrs. at 5 C., the cholesteroldigitonide is separated on a paper filter disc, washed in successionwith 85% ethanol, an acetone-ether mixture (1:2), and anhydrous ether.After drying, the precipitate is counted in a thin window gas flowGeiger Counter and the results recorded as counts per minute per mgm.cholesterol. Comparison with the control gives the index of inhibition.When the active ingredients of this invention are tested by theaforedescribed procedure, a significant inhibition of cholesterolbiosynthesis is usually effected.

A number of compositions found to exhibit outstanding activity inlowering blood cholesterol levels, when tested by the in vivo procedureof Cuthbertson et a1. method described hereinbefore in detail, are shownin Table A. In each instance, the carrier was Diet B containing theactive ingredient in the concentrations stated in the table. Theactivity (percent cholesterol lowering) was obtained in the mannerdescribed hereinbefore, i.e. determining the percent reduction in theblood cholesterol levels by incorporating the active ingredient in DietB as compared to Diet B without the active ingredient.

TABLE A Percent reduction at concen- Oonlrpound Compound ttation ofp-Chlorobenzyloxyamine 46 N -b lgnzyl-N -ben zyloxyamine hydroehlo- 68 ne. Benzyl N-benzyl carbethoxyhydrox- 77 amate. N -beuzyl-N-benzyloxyurea i Benzyl N -benzyl benzhydroxamate- 77 Benzyl N-benzylacethydmxamate" 53 78 N (m-methylbenzyl)-N-(m-methyl- 69 -80 benzyloxy)amine. N-benzyl-N-(m-methylbenzyloxy) amine 81 N-(o-methylbenzyD-N-benzyloxyamine. 74 N (o-methylbenzyl)-N- (o-methylben- 71 86 zyloxy) amine.N-(p-methoxybenzyD-(N-(p-methoxy- 43 benzyloxy) amino. 8 N-('y-phenylpropyl)-N-henzyloxyami.ne 89 hydrochloride. 48 p-ChlorobenzylN-p-ehlorobenzyl car- 80 bethoxyhydroxamate. 41 m-McthylbenzylN-m-methylben zyl 76 73 carbethoxyhydroxamate. 33 Benzytl N-benzylcarbophcnoxyhydrox- 51 80 ama e. 39 o-Methylbenzyl N-o-methylbenzyl car-56 61 bethoxyhydroxamate. 37 Benzyl N-m-methylbenzyl carbethoxy- 2 54 79hydroxamate. 29 Benzy N-benzyl carbomethoxyhydrox- 65 78' ama e. 34-Benzyl N-benzyl carboOS-methoxyeth- 61 oxy) hydroxamate. 32 Benzyl N-benzyl carbo-n-hexyloxyhy- 68 droxamate. i

TAB LE A-C ontinued Percent reduction at concen- Benzyl N-benzylisobntyrhydroxamate Benzyl N-benzyl propionhydroxamate Benzyl N -benzyln-octanohydroxamate Bcnzyl N-o-methylbenzyl acethydroxamate.

N-loenzyl-N-(v-phenylpropoxymmine hydrochloride.

'y-Phenylpropyl N-benzyl carbethoxyhydroxamatc.

'y-Phenylpropyl N -'y-phenylpropyl carbethoxyhydroxamate.

m-Methylbenzyl N -benzyl n-heptanohydroxamate.

m-Methylbenzyl N-m-methylbenzyl acethydroxamate.

1 1% concentration. 1 0.125% concentration.

From the data shown in Table A, it is seen that the preferred activeingredients of this invention may be categorized as follows, referencebeing made to the general structural formulas given hereinbefore: I

(1) Those compounds wherein X is hydrogen, Y is O -iion and Z isaralkyl, as exemplified by the componds 30, 33, 37, 29, 34, 32, 36 and52 shown in Table A;

(2) Those compounds wherein X is hydrogen, Y is ll OR and Z is aralkyl,as exemplified by the compounds 69, 68, 70, 74, 71 and 67 shown in TableA;

(3) Those compounds wherein X is a lower alkyl, Y is t JOOR and Z isaralkyl as exemplified by the compounds 41, 39, 43 and 44 shown in TableA;

(4) Those compounds wherein X is hydrogen, Y is hydrogen and Z isaralkyl as exemplified by the compoundsS, 6 and 8 of Table A;

(5) Those compounds wherein X is lower alkyl, Y is hydrogen and Z isaralkyl, as exemplified by compounds 12, and 11 shown in Table A;

(6) Those compounds wherein X is halogen, Y is and Z is aralkyl, asexemplified by compound 48 shown in Table A;

(7) Those compounds wherein X is hydrogen, Y is Ii --CNH2 and Z isaralkyl, as exemplified by compound 57 shown in Table A;

(8) Those compounds wherein X is halogen, Y is hydrogen and Z ishydrogen, as exemplified by compound 4 shown in Table A;

(9) Those compounds where in X is alkoxy, Y is hydrogen and Z is aralkylas exemplified by compound 16 in Table A;

(10) Those compounds wherein X is alkoxy, Y is and Z is aralkyl asexemplified by compound 46 in Table (11) Those compounds wherein X istnifluoromethyl, Y2 is it C 0 R and Z is aralkyl as exemplified bycompound of Table A.

(12) Those compounds wherein X, is hydrogen, Y is and Z is aralkyl asexemplified by compounds 53 and in Table A;

(13) Those compounds wherein X is lower alkyl, Y is and Z is aralkyl asexemplified by compounds 73 and in Table A;

(14) Those compounds wherein X is hydrogen, Y is hydrogen and Z isaralkyl as exemplified by compound 18 in Table A.

The active ingredients used in accordance with this invention arenon-toxic in amounts required to effect significant reduction of bloodcholesterol. In general, the daily dose of .3 to 20 mg. per pound ofsubject, and, preferably, 1.3 to 6.6 mg. per pound of subject.

Of the preferred active ingredients, the first six compounds listed inTable A are previously described compounds, while' the remaining listedcom-pounds are new compounds.

While a few of the active ingredients used in accordance with thisinvention are previously described compounds, e.g.,N-benZyl-N-benzyloxyamine, for the most part, the active ingredients ofthis invention are novel compounds.

A class of novel compounds of the present invention may be defined ascompounds selected from the group consisting of (1) compounds having thefollowin formula: V

wherein X is selected from the group consisting of lower alkyl andhalogen, Y is selected from the group consisting of hydrogen,

it it it -CR, COR, ONH2 and o 0 II II CNHCR wherein R is selected fromthe group consisting of alkyl and 'aryl; and Z is selected from thegroup consisting of hydrogen and aralkyl; wherein when X in the aboveformula is halogen, Y is selected from the group consisting of hydrogen,

and

r 7 and only one of the Y and Z groups may be hydrogen; and (2)compounds having the formula:

QCHZON/ iOR-1 wherein R is selected from the group consisting of alkyland aryl; and Z is an aralkyl group; and (3) compounds having theformula:

/Y @CLEEON X3 Z2 wherein X is a trifluoromethyl group, Y is selectedfrom the group consisting of and -(OR5 wherein R is selected from thegroup consisting of alkyl and aryl, and Z is selected from the groupconsisting of hydrogen and aralkyl groups. An additional class of novelcompounds of the present invention are compounds of the formula:

wherein X; is selected from the group consisting of hydrogen and loweralkyl; Y is selected from the group consisting of hydrogen and ii GOR3wherein R is selected from the group consisting of alkyl and aryl; and Zis an aralkyl group.

In addition to the above-mentioned compounds, compounds which are noveland may be used as the active ingredient in "accordance with thisinvention are given in Table 1, given hereinafter, said compounds beingalso included in Tables B to H.

In preparing the novel aralkyl carbethoxyhydroxarnate compounds of thisinvention, hydroxyurethane is reacted with the appropriate aralkylhalide (e.g., parachlorobenzyl chloride) under the influence of alkaliin alcoholic solution. By varying the molar ratio of the aralkyl halideto the hydroxyurethane employed one can obtain:

(1) The aralkyl carbethoxyhydroxama-te substantially exclusively, or

(2) a mixture of this compound and the corresponding aralkyl N-aralkylcarbethoxyhydroxamate substantially exclusively.

In general, an equimolar ratio of the reactants leads to the aralkylcarbothoxyhydroxamate compound while the use of a 2:1 molar ratio of thearalkyl halide to hydroxyurethane gives essentially the aralkylN-aralkyl carbethoxyhydroxamate. Such latter procedure is preferred toproduce carbethoxyhydroxarnate compounds which contain two identicalaralkyl groups.

Alternately, novel aralkyl carboalkyl(aryl)oxyhydroxamates of thisinvention can be obtained by the reaction of an appropriatearalkoxyamine with an alkyl or aryl 8 chloroformate in a suitable inertorganic solvent medium. Similarly, novel aralkyl N-aralkylcarboalkyl(aryl)oxyhydroxam-ates can be prepared from N-aralkylaralkoxyamines and the appropriate chloroformate.

Moreover, novel aralkyl N-aralkyl carboalkyl(a-ryl)- oxyhydroxamates ofthis invention may be obtained by the reaction of the appropriatearalkyl carboalkyl(aryl)- oxyhyd'roxa-mate with a suitable aralkylhalide in alcoholic solution in the presence of alkali. Such reaction isoperable in the production of carb-oalkyl(aryl)oxyhydroxamate compoundsWhich contain either identical or dissimilar aralkyl groups.

The aralkoxyamine compounds and the N-aralkyl aralkoxyamine compounds ofthis invention may be obtained by alkaline hydrolysis of thecorresponding carbethoxyhydroxamate.

In preparing the novel aralkyl acyl(aroyl)hydroxamates and aralkylN-aralkyl acyl(aroyl)hydroxamates of this invention, the selectedaralkoxyamine or N-aralkyl aralkoxyamine is reacted with the appropriateacyla-ting or aroylating agent, such as acyl or aroyl halide, in asuitable aqueous or non-aqueous medium. An excess of the amine or othersuitable base (e.g., pyridine, sodium hydroxide, trialkylamine) may beemployed as acid acceptor to promote the reaction.

Substituted N-aralkoxy ureas or N-aralkyl-N-aralkoxy ureas can beobtained by the reaction of suitable aralkoxyamines or N-aralkylaralkoxyamines with isocyanic acid esters or other derivatives ofisocyanic acid in an inert solvent medium.

Some of the benzyl carboalkyl(aryl)oxyhydroxamates and benzyl N-aralkylcarboalkyl(-aryl)oxyhydroxamates comprising the active ingredients ofthis invention have also been referred to in the chemical literature assubstituted N-benzyloxy urethanes and substituted N-benzyloxy-N-aralkylurethanes. The description of these compounds are used herein isconsistent with Beilstein and other recognized authorities on organicchemical nomenclature.

The following are specific examples for the preparation of activeingredient compounds and therapeutic compositions formed in accordancewith this invention.

EXAMPLE I Preparation of o-chlorobenzyloxyamine hydrochloride(compound 1) A solution of 11.7 grams of o-chlorobenzylcarbethoxyhydroxamate and 6.2 grams of sodium hydroxide in 50% aqueousethanol was refluxed for two hours. The ethanol was removed bydistillation and the residue extracted with ether. This extract waswashed with water and dried over sodium sulfate. The addition ofconcentrated hydrochloric acid resulted in the precipitation of thedesired compound. Recrystallization from methanol gave 3.5 grams of thepure hydrochloride, M.P. 143-145". Other compounds prepared using thisprocedure were benzyloxyamine hydrochloride (compound 2);m-methylbenzyloxyamine (compound 3); and p-chlorobenzyloxyamine(compound 4). The latter two compounds were isolated as the free aminesand were purified by distillation under reduced pressure. Thesecomponents had the physical constants and analytical values tabulated inTable B given hereinafter.

EXAMPLE II Preparation of N-benzyloxyamine hydrochloride (compound 5)N-benzyl-N-benzyloxyamine is converted to its hydrochloride salt by theaddition of an excess of concentrated hydrochloric acid to an ethersolution of the amine. The product, which separates in the form of aslightly watersoluble crystalline solid, is purified by crystallizationfrom methanol.

9 EXAMPLE III Preparation ofN-(p-methylbenzyl)-N-(p-methylbenzylxy)amine (compound 13) A solution of14.6 grams of p-methylbenzyl N-p-methylbenzyl carbethoxyhydroxamateprepared by the method described in Example VII and 6.8 grams of sodiumhydroxide in 300ml. of 95% ethanol and 100 ml. of water was refluxed forone and one-half hours. The reaction mixture was then concentrated undervacuo and then poured into water. N-(p-methylbenzyl) Np-methylbenzyloxy)amine in the form of a water-insoluble material wasfiltered ofl, thoroughly washed with water, and then crystallized frommethanol. Yield 8.3 grams, M.P. 860 C. N-(p-methylbenzyl)-N-(pmethylbenzyloxy)amine is converted to its hydrochloride salt by theaddition of an excess of concentrated hydrochloric acid to an ethersolution of the amine. The product, which separates in the form of aslightly water-soluble crystalline solid, is purified by crystallizationfrom methanol, M.P. 188-190" C.

EXAMPLE IV Preparation ofN-(p-isopropylbenzyl)-N-(p-isopr0pylbenzyloxy)amine hydrogen sulfate(compound 14) A solution of 63 grams of p-isopropylbenzylN-p-isopropylbenzyl carbethoxyhydroxamate prepared by the method ofExample VII and grams of sodium hydroxide in 400 m1. of 50% aqueousethanol was refluxed for two hours. The mixture was distilled atatmospheric pressure until the head temperature was 100 C. The residuewas extracted with ether. This extract was washed with water untilneutral and was dried over sodium sulfate. The resulting solution wasadded slowly to a cool solution of 17 grams of sulfuric acid in 200 ml.of anhydrous ether. The desired compound precipitated in the form ofcolorless crystals. The yields was 39 grams.

EXAMPLE V Preparation of N-(rn-methylbenzyl)-N-(m-methylbenxyloxy)amine(compound 12) EXAMPLE VI Preparation of N m-methylbenzyl -N -['y-(p-tolyl propoxy]amine (compound 20) (A) To a solution of sodium ethylateprepared from 23 grams of sodium metal and 1000 ml. of anhydrous ethanolthere was added 105 grams of N-hydroxy urethane and 213 grams of1-bromo-3-(p-tolyl)-propane and the mixture was refluxed for four hours.A major portion of the ethanol solvent was then removed by distillationat atmospheric pressure until the head temperature reached 86 C. To thecooled residue there was added 250 ml. of water and 250 ml. of ether,the ether layer was separated and-the aqueous layer was extracted withan additional 200 ml. of ether. The pooled ether extracts were washedwith water until neutral and dried over sodium sulfate. The ether wasremoved and the residue distilled in vacuo. There was obtained 118 gramsof 'y-(p-tolyDpropyl carbethoxyhydroxamate having the following physicalproperties: B.P. 155/0.3 mm., n 1.5060.

Analysis (for C H NO ).Calculated: C, 65.80; H, 8.07; N, 5.90. Found: C,65.97; H, 8.14; N, 6.12.

(B) 35.1 grams of the above 'y-(p-tolyDpropyl carbethoxyhydroxamate wasadded to a solution of sodium ethylate prepared from 3.4 grams of sodiummetal and 200 ml. of anhydrous ethanol. To the reaction mixture therewas then added 27.4 grams of m-xylyl bromide and the mixture wasrefluxed for four hours. At the end of such period a solution of 12.8grams of sodium hydroxide in 130ml. of water was added to the reactionmixture and refluxing was continued for an additional period of twohours. The ethanol was removed by distillation at atmospheric pressureuntil the head temperature reached 86 C. and the cooled residue wasextracted with 500 ml. of ether. The ether extract was washed with wateruntil neutral and dried over sodium sulfate. The ether was removed andthe residue distilled in vacuo. The fraction boiling at about 142/ 0.08mm. consisted of the desired N-(m-methylbenzyl)-N-['y-(p-to1yl)-propoxy]amine. The yield was 29.6 grams.

The physical properties and analytical values for the compounds preparedin Examples IIVI and of other compounds which can be prepared bysubstantially similar methods are summarized in Table C given hereafter.

EXAMPLE VII Preparation of p-chlorobenzyl N-p-chlorobenzylcar-bethoxyhydroxamate (compound 48) and p-chlorobenzylcar-betlzoxyhydroxamate (compound 27) 52.5'grams of hydroxyurethane in500 ml. of ethanol are combined with stirring at 25 C. with a solutionof 56 grams potassium hydroxide in ml. of 95% ethanol. 121 grams ofp-chlorobenzyl chloride is added at once and the temperature maintainedat about 30 using external cooling. The mixture is stirred overnight andthe potassium chloride removed by filtration. The filtrate isconcentrated in vacuo and dissolved in 400 ml. of ether. The ethersolution is extracted thoroughly with cold 10% aqueous sodium hydroxide.The resulting ether solution is dried, the solvent removed and theresidue distilled under reduced pressure. 45 grams (25% theoretical) ofp-chlorobenzyl N-p-chlorobenzyl carbethoxyhyroxamate is obtained.

The aforedescribed sodium hydroxide extract is acidi-' fied withhydrochloric acid while cooling. The mixture is then extracted withether, the ether solution dried, the solvent evaporated, and a solidresidue obtained. This product is purified by crystallization fromethanol. 34.5 grams (30% theoretical) of p-chlorobenzylcarbethoxyhydroxamate is obtained in the form of white crystals.

EXAMPLE VIII Preparation of m-methylbenzyl carbethoxyhydroxama te(compound 26) and m-methylbenzyl N-m-methylbenzyl carbethoxyhydroxmate(compound 41) 38 grams of hydroxyurethane in ml. of 95% ethanol, 36grams of potassium hydroxide in-200 ml. of 95% ethanol, and 100 grams ofalpha-bromo-m-xylene were reacted as described in Example VII above. Theether extract was dried, freed from solvent by distillation, and theresidue fractionated under reduced pressure. 17 grams (22%) of purem-methylbenzyl carbethoxyhydroxamate was obtained distilling at 100-103at'0.05 mm.

Further distillation of the aforedescribed residue yielded 38.5 grams(34%) of m-methylbenzyl N-m-methylbenzyl carbethoxyhydroxamate. B.P.144146 at 0.05 mm. Hg.

EXAMPLE IX Using the method described in Example VII, hydroxyurethaneand p-methylbenzyl chloride wererea'cted to give p-methylbenzylN-p-methylbenzyl carbethoxyhydroxamate (compound 42). The purifiedproduct was obtained as a colorless liquid distilling at 137 at 0.1 mm.Hg.

1 1 EXAMPLE x EXAMPLE XI Preparation of m-trifluoromethylbenzylcarbethoxyhy droxamate (compound 28) A solution of sodium ethylate wasprepared by dissolving 6.8 grams of sodium metal in 500 ml. of anhydrousethanol. To this was added with cooling 31.2 grams of hydroxyurethaneand subsequently with continued cooling 71 grams ofm-trifluormethylbenzyl bromide. The temperature did not exceed 30 C.during these operations. The mixture was stirred for 30 minutes at roomtemperature and for two hours at reflux temperature. The mixture wasdiluted with 250 ml. of water and neutralized by the addition ofhydrochloric acid. The ethanol was removed by distillation and theresidue was extracted with ether. This extract was washed with dilutehydrochloric acid and with water and was dried over sodium sulfate.Evaporation of the ether furnished a solid residue which afforded, uponrecrystallization from carbon tetrachloride, 38 grams of the purecompound, M.P. 78-80 C.

The m-trifluoromethylbenzylbromide used in this example as well as otherbenzylhalides can be prepared by halogenation of the correspondingbenzyl alcohols or toluenes using well-known reactions. The physicalconstants and analytical values for the compounds of Examples VII-XI andfor compounds 21- 23 and 25, which may be prepared using these methods,are summarized in Table D given hereinafter, and in part in Table Egiven hereinafter.

EXAMPLE XII Preparation of benzyl N-benzyl carbethoxyhydroxamate(compound 30) A solution of 210 grams of hydroxyurethane and of 460 ml.of benzyl chloride in 1 liter of ethanol was heated to reflux. One literof a 4-N solution of potassium hydroxide in ethanol was added withinfour hours. Subsequently, 1.5 liters of ethanol was removed by distillation and the residue was diluted with 1 liter of ether. Thesolution was decanted from the inorganic salts which were washed withthree portions of ether. The combined solution was stirred while 30 ml.of concentrated hydrochloric acid was added. The mixture was filteredand the filtrate was washed with dilute bicarbonate solution and wateruntil neutral. The resulting ether solution was dried over sodiumsulfate and the ether was removed by distillation. Fractionation of theresidue in vacuo furnished 382 grams of the desired compound distillingat 142-145 C./0.3 mm.

EXAMPLE XIII Preparation of benzyl N-benzyl oarbophenoxyhydroxamate(compound 33) A solution of 42.6 grams of N-benzyl-N-benzyloxyamine in100 ml. of anhydrous ether was added dropwise to a cooled solution of15.7 grams of phenyl chloroformate in 500 ml. of anhydrous ether. Theresulting mixture was stirred for three hours at room temperature. Thesolid precipitate was removed by filtration and the 12 filtrate wasevaporated in vacuo. The residue solidified upon standing at roomtemperature. Recrystallization from methanol furnished 26.6 grams of thedesired compound, M.P. 59-61 C.

EXAMPLE XIV Preparation of o-methylben-zyl N-o-methylbenzylcarbethoxyhydroxamate (compound 39) Solutions of 28.4 grams ofhydroxyurethane in 150 ml. of ethanol and of 35.7 grams of potassiumhydroxide in 250 ml. of ethanol were combined at room temperature. 100grams of alpha-bromo-o-xylene was added dropwise with stirring while thetemperature was maintained at 2530 C. by external cooling. Subsequently,the mixture was heated to reflux and the ethanol was removed bydistillation until the vessel temperature had reached C. The residue wasdiluted with ether and was filtered from the inorganic salts. Theresulting solution was washed with water and dried over sodium sulfate.The ether was removed by distillation and the residue was fractionatedunder vacuum. The fraction boiling at 143/ 0.04 consisted of the desiredcompound. Yield 59.4

grams.

EXAMPLE XV Preparation of benzyl N-m -methylbenzyl carbethoxyhydroxamate(compound 37) A solution of sodium ethylate was prepared from 2.3 gramsof sodium metal and 200 ml. of anhydrous ethanol. To this was added 19.5grams of benzyl carbethoxyhydroxamate and subsequently there was addedwith cooling and stirring 18.5 grams of alpha-bromo-m-xylene over aperiod of 15 minutes. The mixture was heated to reflux for two hours andthe ethanol was removed by distillation until the vessel temperaturereached 85 C. The residue was diluted with water and was extracted withether. This extract was Washed with water and was dried over sodiumsulfate. The ether was removed by distillation. Fractionation of theresidue in vacuo furnished 18.3 grams of product, B.P. 136 C./0.02'mm.

EXAMPLE XVI Preparation of 'y-(p-tolyl)-pr0pyl-N-m-methylbenzylcarbophenoxyhydroxamate (compound 54) To a solution of 3.0 grams ofpyridine and of 10.2 grams of N-(m-methylbenzyl-N-['y-(p-tolyD-propoxy]amine, prepared as described in Example VI, in ml. of anhydrous etherthere was added, in three portions, 5.9 grams of phenyl chloroformate.The reaction temperature was maintained below 35 C. during the additionby external cooling means. The mixture was kept at room temperatureovernight. To the mixture there was added ml. of ether and 75 ml. ofwater, the ether layer was separated and the aqueous layer was furtherextracted with 100 ml. of ether. The combined ether extracts were washedwith 5% hydrochloric acid and then with Water until neutral. The ethersolution was dried over sodium sulfate and the ether was removed in arotary evaporator. The residue was heated under a pressure of 0.07 mm.until the temperature of the vapors reached 90 C. and then distilled invacuo in a molecular distillation unit. There was obtained 10.5 grams ofthe desired product at a bath temperature of 159 C. and at a pressure of0.001 mm.

EXAMPLE XVII 'y-Phenylpropyl-N-y-phenylpropyl carbethoxyhydroxamate(compound 55) temperature reached 85 C. The cooled residue was dilutedwith 200 ml. of water and the aqueous mixture was extracted with 500 ml.of ether. The ether extract was washed with small quantities of dilutesodium hydroxide solution until the color test with ferric chloride wasnegative, then washed with small quantities of water until neutral anddried over sodium sulfate. The ether solvent was removed and the oilyresidue distilled in vacuo. The fraction collected at 138 C./0.2 mm.consisted of 102 grams of Y-phenylpropyl carbethoxyhydroxamate, n1.5070.

Analysis (for C H NO was as following.-Calculated: C, 64.55; H, 7.67; N,6.27. Found: C, 64.37; H, 7.20; N, 6.46.

Continued distillation of the residue yielded 41 grams of 'yphenylpropyl N ('y phenylpropyl)carbethoxyhydroxamate, B.P. 182 C./.2mm.

The physical constants of the compounds prepared in Examples XII-XVII,as well as those of other compounds which can be prepared bysubstantially similar methods, are summarized in Table E givenhereinafter.

EXAMPLE XVIII Preparation of N-benzyloxy urea (compound 56) A solutionof 4.5 grams of potassium cyanate in 50 I111. of water was added to astirred slurry of 8.0 grams of benzyloxyamine hydrochloride in 150ml. ofwater. Stirring was continued for minutes and the colorless solid wasfiltered and washedwithwater. Recrystallization from ethanol furnished4.9 grams of the desired product, M.P. 139-141 C.

EXAMPLE XIX Preparation of N-benzyl-N-benzyIoxy-N-acetyl urea (compound59) Solutions of 21.3 grams of N-benzyl-N-benzyloxyamine in 300 ml. ofanhydrous ether and of 8.5 grams of acetyl isocyanate in 200 ml. ofanhydrous ether were combined at room temperature. The mixture wasallowed to stand overnight and the ether was removed by distillation.The solid residue was extracted exhaustively with pentane. The extractyielded 22.4 grams of the desired compound, M.P. 6162 C.

The physical constants and analytical values for these compounds, andfor compounds 57 and 58, prepared using the same methods, are tabulatedin Table F given hereinafter.

EXAMPLE XX Preparation of benzyl acethydroxamate (compound 60) Asolution of 31.7 grams of acetyl chloride in 50 ml. of anhydrous etherwas added dropwise with stirring to a solution of 98.7 grams ofbenzyloxyamine in 400 ml. of anhydrous ether. The mixture was stirredfor two hours at room temperature. The precipitate of benzyloxyaminehydrochloride was removed by filtration and was washed with ether. Thecombined filtrates were evaporated at atmospheric pressure and theresidue was fractionated in vacuo. The fraction distilling at 109/0-.2mm. consisted of the desired compound. Yield 42.4

grams.

Other compounds prepared by this method using the appropriate acidchloride were compounds 61-66. Analytical data and physical constantsfor these compounds appear in Table G given hereinafter.

EXAMPLE XXI Preparation of benzyl N-benzyl isobutyrhydroxamate (compound69) A solution of 32 grams of N-benzyl-N-benzyloxyamine in 50 ml. ofanhydrous ether was added with stirring and cooling to a solution of 8grams of isobutyryl chloride in 150 ml. of anhydrous ether. The mixturewas stirred for two hours and the precipitate was filtered and washedwith ether. The combined filtrate was evaporated and 14 the residue wasfractionated in vacuo. The fraction distilling at 133-136" C./0.1 mm.consisted of the desired compound. The yield was 14.6 grams.

EXAMPLE XXII Preparation of m-trifluoromethylben'zylN'-m-triflu0romethylbenzyl acethydroxamate (compound '82) 1.10 parts ofN-(rn-trifluoromethylbenzyl)-N-(m-trifluoromethylbenzyloxy)aminehydrochloride was dissolved in 25 parts of pyridine and 0.9 part ofacetyl chloride was added with cooling. The mixture was kept overnightat room temperature and was poured into an excess of cold water. Theoily precipitate was extracted with ether and the extract washed withdilute hydrochloric acid and water. The extract was dried over sodiumsulfate and the solvent evaporated. The oily residue was distilledunderreduced pressure in a short path unit at C./0.002 mm. The distillateconsisted of the pure title compound. The yield was 0.8 parts of pureproduct.

EXAMPLE XXIII Preparation of p-chlorobenzyl N-p-clzlorobenzylberlzhydroxamate (compound 81) A mixture of 25.4 grams ofN-(p-chlorobenzyD-N-(pchlorobenzyloxy) amine hydrochloride, 200 ml. ofwater, 14 ml. of 50% sodium hydroxide, 250 ml. of ether, and 12.3 gramsof benzoyl chloride was stirred vigorously for two hours. The etherlayer was separated and was washed with dilute sodium hydroxide, Water,dilute hydrochloric acid and again with water until neutral. The etherwas dried over sodium sulfate and the solvent was removed bydistillation. The residue solidified upon cooling. Recrystallizationfrom ethanol furnished 22.5 grams of the desired compound.

The physical constants and analytical values for the compounds preparedin Examples XXL-XXIII, as well as those of other compounds prepared bysubstantially similfar methods, are summarized in Table E hereinafterset orth.

The following are examples of compositions formed in accordance withthis invention which have the effect of lowering blood cholesterol uponadministration 'of such compositions in warm-blooded animals.

EXAMPLE XXIV A tablet is compressed from a composition having thefollowing formula:

EXAMPLE XXV Alta blet is compressed from a composition having thefollowing formula:

N- (p methylbenzyl -N- (p-methylbenzyloxy) M gm.

amine hydrochloride 200 Corn starch 20 Lactose 20 Magnesium stearate 2Alginic acid 4 EXAMPLE XXVI A tablet is compressed from a compositionhavingthe following formula:

Mgm. N-benzyl-N-benzyloxy urea 200 Corn starch 20 Lactose 20 Magnesiumstearate 2 Alginic acid 4 1 EXAMPLE xxvtr A tablet is compressed from acomposition having the following formula:

Mgm. p-Chlorobenzyl carbethoxyhydroxamate 200 Corn starch a 20 Lactose20 Magnesium stearate 2 Alginic acid 4 EXAMPLE XXVIII 100 mg. ofm-methylbenzyl N-m-methylbenzyl carbethoxyhydroxamate is mixed with 1.5cc. of cottonseed oil and the resulting solution is encapsulated in asoft gelatin capsule.

EXAMPLE XXIX 200 mg. of benzyl N-benzyl carbethoxyhydroxarnate is mixedwith 0.5 cc. of cottonseed oil and resulting solution is encapsulated ina soft gelatin capsule.

EXAMPLE XXX 200 mg. of N-benzyl-N-benzyloxyamine is mixed with an equalvolume of polyethylene glycol 400 and the resulting solution isencapsulated in a soft gelatin capsule.

EXAMPLE XXXI 200 mg. of N-benzyl-N-benzyloxyamine hydrochloride is mixedwith an equal volume of polyethylene glycol 400 and the resultingmixture is encapsulated in a soft gelatin capsule.

EXAMPLE XXXII 200 mg. of benzyl carbethoxyhydroxamate is mixed with anequal volume of polyethylene glycol 400 and the resulting solution isencapsulated in a soft gelatin capsule.

EXAMPLE XXXIII 200 mg. of m-rnethylbenzyl carbethoxyhydroxamate is mixedwith an equal volume of propylene glycol and the resulting solution isencapsulated in a soft gelatin capsule.

EXAMPLE XXXIV 200 mg. of p-chlorobenzyl N-p-chlorobenzylcarbethoxyhydroxamate is mixed with 0.5 cc. of cottonseed oil and theresulting solution is encapsulated in a soft gelatin capsule.

' EXAMPLE XXXV 4 t 100 mg. of p-methylbenzyl N-p-methylbenzylcarbethoxyhydroxamate is mixed with 1.5 cc. of cottonseed oil and theresulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XXXVI A tablet is compressed from a composition having thefollowing formula:

Mgm. Benzyl N-benzyl carbophenoxyhydroxamate, 360 Corn starch 20 Lactose70 Magnesium stearate 40 Dicalcium phosphate 40 EXAMPLE XXXVII A tabletis compressed from a composition having the following formula:

1 6 EXAMPLE' XXXVIII A tablet is compressed from a composition havingthe following formula:

' Mgm. Benzyl N-benzyl acethydroxamate 400 Corn starch 25 Lactose i 25Magnesium stearate '4 Alginic acid v 1O EXAMPLE XXXIX 250 mgm. of benzylN-benzyl isobutyrhydroxamate is mixed with an equal weight ofpolyethylene glycol 400 and the resulting solution is encapsulated in asoft gelatin capsule.

EXAMPLE XL A tablet is compressed from a composition having thefollowing formula:

I Mgm.

N- ('y-phenylpropyD-N benzyloxyamine hydrochloride 250 Corn starch 20Lactose 70 Magnesium stearate 2 Dicalcium phosphate 50 EXAMPLE XLI 200mgm. of N-benzyl-N-(m-methylbenzyloxy)amine is mixed with 0.25 cc. ofcorn oil and the resulting solution is encapsulated in a soft gelatincapsule.

EXAMPLE XLII 200 mgm. of p-chlorobenzyloxyamine is mixed with 0.25 cc.of corn oil and the resulting solution is encapsulated in a soft gelatincapsule.

EXAMPLE XLIII mgm. of p-methoxybenzyl N-p-methoxybenzyl'carbethoxyhydroxarnate is mixed with 0.5 cc. of corn oil and theresulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XLIV 300 mgm. of m-trifiuoromethylbenzylN-m-trifiuoromethylbenzyl carbethoxyhydroxamate is mixed with an equalvolume of propylene glycol and the resulting mixture is encapsulated ina soft gelatin capsule.

EXAMPLE XLV 200 mgm. 'of benzyl N-benzyl carbo(l3-methoxyethoxy)hydroxamate is mixed with 0.5 cc. of corn oil and the resulting solutionis encapsulated in a soft gelatin capsule.

EXAMPLE XLVI 250 mgm. of p-isopropylbenzyl N-(p-isopropylbenzyl)carbethoxyhydroxamate is mixed with 0.5 cc. of corn oil and theresulting solution is encapsulated in a soft gelatin capsule.

EXAMPLE XLVII 200 mgm. of 'y-phenylpropylN-(y-phenylpropyhcarbethoxyhydroxamate is mixed with 0.25 cc. of cornoil and the resulting solution is encapsulated in a soft gelatincapsule.

'Found ,s'rs

Analysis 1 Calculated A-ONH2 17 Tables B to I, mentioned hereinbefore,

TABLEHB Formula The following are now given TABLE H ll C-R X Z AnalysisM.P., or n No. X A R Z Formula 13 .P./mm. Calculated Found 0 H N c 1 H NBenzyl C1aH11NO2 57-58 75. 27 6. 71 5. 49 75. 29 Q 7. 25 5. 61 doC11HmNOz.- 146/0. 1 1. 5535 75. 81 7. 11 5. 20 75. 87 7. 00 5. 41 doCrsH21NO2 136/0. 1 1. 5470 76. 29 7. 47 4. 94 76. 50 7. 45 5. 02 -do-O22II29NOZ 167/0. 2 1. 5306 78. 00 8. 63 4. 13 78.06 8. 53 4. 19 d0C21I-ImNOz. 65-67 79.47 6. 04 4. 41 79. 22 6. 23 4. 59 .do. C17HmNO238-40 75. 81' 7. 11 5. 20 75. 86 '6. 99 5. 14 do C22H2uNO2 125/0. 01 1.5308 p 78. 00 8. 63 4. 13 '77. 90 8. 62 4 19 o-MethylbenzylCl7Hl0NO2.--- 66-68 75. 81 7. 11 75. 33 7. 01 5. 31 m-Methylbenzyl-ClxI'IflNOz.-.. 125/0. 01 1. 5534 76. 29 7. 47 4. 94 76. 12 7. 66o-Methylhenzyl- C2aH2sNO2 93-95 79. 97 6. 71 4. 06 79. 44 6. 60 4 28 d0C2uH25NO2 147/0. 03 1. 5471 77. 13 8. 09 4. 50 76. 95 81 15' 4. 283,4dnnethylbenzyl..- C2oH25NOz 110/0. 01 1. 5554 77. 13 8. 09 4. 50 76.81 7. 83 p-Methoxybenzyl Cz0H25NO4 150/0. 1 1. 5499 69.94 7. 34 4. 0870. 11 7. 31 4. p-Ghlol'obenzyL CiaHrsClrNOz- 41-44 59. 28 4. 66 .21. 8759. 14 4. 01 22. 19 d0 CzrHnClzNOz- 79-82 65. 4. 44 18. 65. 07 4. 56 18.51 m-CF3-benzylomHumNon. 90/0. 02 1. 4845 55. 25 3. 86 3. 58 55. 19 3.68 3. 'y-Phenylpropyl C2sH23NO2..- 130/0. 2 1. 5812 79. 97 6. 71 4. 0679. 39 7. 16 4. 23

! Chlorine.

TAB LE I gen, lower alkyl and halogen; Y is selected from the groupconsisting of hydrogen, Compound Compound 30 (3 R, -o o R, --CNHN-(o-methylbenzyl)-N benzyloxylamine. d N-(B-phenethyl)-N-benzyloxyamine. an N-(v-phenylpropyl)-N-benzyloxyamine hydrochloride.p Benzyl earboisobutoxyhydroxamate. 3o

Benzyl carbomethoxyhydroxamate.

Benzyl carbo-n-butoxyhydroxarnate.

Benzyl earbophenoxyhydroxamate.

p-Chlzorobenzyl N-p-chlorobenzyl carbethoxyhydroxa ma e.

Benzyl N-benzyl carbophenoxyhydroxamate.

' Benzyl N-nl-methylbenzyl carbethoxyhydroxamate.

Benzyl N-benzyl carbomethoxyhydroxamate. Benzyl N-benzyl carbo(,B-rnethoxyethoxy) hydroxamate. Benzyl N-benzylearboisobutoxyhydroxamate. Benzyl N-benzyl carbo-n-hexyloxyhydroxamate.Benzyl N-o-methylbenzyl carbethoxyhydroxamate. p-ChlorobenzylN-p-chlorobenzyl carbomethoxyhydroxamate. p-ChlorobenzylN-p-chlorobenzyl carbophenoxyhydroxamate. Benzyl N-B-phenethylcarbethoxyhydroxamate. Benzyl N -phenylpropyl carbethoxyhydroxamate.N-benzyl-N-benzyloigy-N{-aeetyl urea. N-b'enzyloxy N acetyl urea. Benzylisobutyrhydroxamate.

Benzyl n-nonanohydroxamate.

Benzyl n-tetradeeanohydroxamate.

Benzyl n-hexadeeanohydroxamate.

Benzyl n-butyrhydroxamate.

Benzyl N-benzyl isobutyrhydroxamate.

Benzyl N-benzyl n-propionohydroxamate.

Benzyl N -benzy1 n-octanohydroxamate.

Benzyl N -o-rnethoxylbenzyl aeethydroxamato.

Benzyl N-( -phenylpropyl) benzhydroxamate.

formula:

wherein X is selected from the group consisting of hydro wherein R isselected from the group consisting of alkyl and phenyl; and Z isselected from the group consisting of hydrogen and phenyl short-chainalkyl; 2) compounds having the formula:

Q-ornor/ wherein X is lower 'alkoxy; Y is selected from the groupconsisting of hydrogen,

and

wherein X is trifiuorometliyl; Y is selected from the group consistingof and wherein R is selected from the group consisting of alkyl andphenyl; and Z is selected from the .group consisting of hydrogen andphenyl short-chain alkyl.

23 2. The method according to claim 1 wherein in the formula tor theactive ingredient, X is hydrogen, Y is u -COR and Z is phenylshort-chain alkyl.

3. The method according to claim 1 wherein in the formula for the activeingredient, X is hydrogen, Y is v V Y.

ll CR and Z is phenyl short-chain alkyl.

4. The method according to claim 1 wherein in the formula for the activeingredient, X is lower alkyl, Y is 0 [I --COR and Z is phenylshort-chain alkyl.

5. The method according to claim 1 wherein in the formula for the activeingredient, X is hydrogen, Y is hydrogen, and Z is phenyl short-chainalkyl.

6. The method according to claim 1, wherein in the formula for theactive ingredient, X is lower alkyl, Y is hydrogen and Z is phenylshort-chain alkyl.

7. The method according to claim 1, wherein in the formula for theactive ingredient, X is halogen, Y is and Z is phenyl short-chain alkyl.

8. The method according to claim 1, wherein in the formula for theactive ingredient, X is hydrogen, Y is and Z is phenyl short-chainalkyl.

9. The method according to claim 1, wherein in the formula for theactive ingredient, X is halogen, Y is hydrogen and Z is hydrogen.

10. The method according to claim 1, wherein in the formula for theactive ingredient, X is lower alkoxy, Y is hydrogen and Z is phenylshort-chain alkyl.

11. The method according to claim 1, wherein in the formula for theactive ingredient, X is lower alkoxy, Y

i -COR1 and Z is phenyl short-chain alkyl.

12. The method according to claim 1, wherein in the formula for theactive ingredient, X is trifluoromethyl, Y2 is i1OR 2 and Z is phenylshort-chain alkyl.

13. The method according to claim 1, wherein the active ingredient isselected from the group consisting of: p-chlorobenzyloxyamine,N-benzyl-N-benzyloxyamine hydrochloride, benzyl N-benzylcarbethoxyhydroxamate, N- benzyl-N-benzyloxy urea, benzyl N-benzylbenzhydroxamate, benzyl N-benzyl acethydroxamate, N-(m-methyL gbenzyl)-N-'(m-rrrethylbenzyloxy) amine, N #benzyl-N- (mmethylbenzyloxy) amine,N-(o-methylbenzyl) -N-benzyloxyamine,N-(o-methylbenzyl)-N-(o-methylbenzyloxyamine hydrochloride,N-(p-methoxybenzyl)-N-(p-methoxybenzyloxy) amine, N-(v-phenylpropyl)-N-benzyloxyamine hydrochloride, pachlorobenzyl N-p-rC'hlOI'ObGIIZYlcarbethoxyhydroxamate, m-methylbenzyl Nm-methylbenzylcarbethoxyhydroxamate, benzyl N-benzyl carbophenoxyhydroxarnate,o-methylbenzyl N-o-methylbenzyl carbethoxyhydroxamate, benzylN-m-methylbenzyl carbethoxyhydroxamate, benzyl N-benzylcarbomethoxyhyd-roxamate, benzyl N-benzyl carbo (B-methoxyethoxy)hydroxamate, benzyl N-benzyl carbo-n-hexyloxyhydroxamate, benzyl N omethylbenzylcarbethoxyhydrox- 24 amate, o-ethylbenzyl N-o-ethylbenzylcarbethoxyhyd-roxamate, p-isopropylbenzyl N-p-isopropylbenzylcarbethoxyhydroxamate, m-trifluoromethylbenzylN-rn-trifluoromethylbenzyl carbethoxy hydroxamate, p-methoxybenzyl N-p-methoxybenzyl carbethoxyhydroxamate, benzyl N-yphenylpropylcarbethoxyhydroxamate, benzyl N-benzyl isobutyrhydroxamate, benzylN-benzyl propionhydroxamate, benzyl N-benzyl n-octanohydroxamate, andbenzyl N-o-methylbenzyl acethydroxamate.

14. A method of reducing the blood cholesterol content of a warm-bloodedanimal having excess cholesterol which comprises administeringinternally to said animal, in an amount sufficient to effect significantlowering of the blood cholesterol content of said animal a compound ofthe formula:

@ornornornor wherein X is selected firom the group consisting ofhydrogen and lower alkyl; Y is selected from the group consisting ofhydrogen and OOR,

wherein R is selected from the group consisting of alkyl and phenyl; andZ is phenyl short-chain alkyl.

15. The method according to claim 14 wherein in the formula for theactive ingredient, X is hydrogen, Y is i C 0 R3 and Z is phenylshort-chain alkyl.

16. The method according to claim 14 wherein in the formula for theactive ingredient, X is hydrogen, Y is hydrogen and Z is phenylshort'chain alkyl. 7

17. The method according to claim 14 wherein the ac tive ingredient isNbenz yl-N-('y-phenylpropoxy) amine hydrochloride.

18. The method according to claim 14 wherein the active ingredient is'y-p'henylpropyl N-benzyl carbethoxyhydroxamate.

19. The method according to claim 14 wherein the active ingredient is'y-phenylpropyl N-y-phenylpropyl carbethoxyhydroxamate.

References Cited by the Examiner UNITED STATES PATENTS 2,695,913 11/1954 Bloch et a1. 260-471 2,816,059 12/1957 Mills 167-65 2,819,294 1/1958 Pechukas et al. 260-471 2,830,008 4/1958 Barber et al. 167-652,970,082 1/ 1961 Miale 167-65 I 2,978,381 4/ 1961 Freedman 167-65 OTHERREFERENCES JULIAN S. LEVITT, Primary Examiner.

FRANK CACCIAPAGLIA, JR., Examiner.

1. A METHOD OF REDUCING THE BLOOD CHOLESTEROL CONTENT OF A WARM-BLOODEDANIMAL HAVING EXCESS CHOLESTEROL WHICH COMPRISES ADMINISTERINGINTERNALLY TO SAID ANIMAL, IN AN AMOUNT SUFFICIENT TO EFFECT SIGNIFICANTLOWERING OF THE BLOOD CHOLESTEROL CONTENT OF SAID ANIMAL, A COMPOUNDSELECTED FROM THE GROUP OF (1) COMPOUNDS HAVING THE FORMULA: